Over many years, our laboratory has consistently observed significantly lower amplitudes of Event-Related Potential (ERP) components, particularly the visual P3(00), in abstinent alcoholics. In the last grant period we have identified other specific neurophysiological anomalies, notably decreased event-related frontal theta, delta and gamma band responses during cognitive tasks. Recently, we have found that some of these deficits are also predictive of relapse. We have also demonstrated that alcoholics manifest a lack of electrophysiological differentiation regardless of stimulus and task requirements for several measures, and respond more generically to different cognitive demands in a task. Most of these deficits are more related to risk (family history of alcoholism) than excessive alcohol intake, and are thus already present in high risk offspring of alcoholics prior to alcohol exposure. Our preliminary studies also indicate anomalies in neural synchrony in resting brain states in alcoholics, and impairments in synchronization during cognitive operations. We have proposed that increased Central Nervous System disinhibition may underlie these anomalies and a predisposition to develop alcohol dependence and related disorders. We have recently found that P3 amplitude is related to level of impulsivity in alcoholics, and individuals with increased impulsivity manifest reduced activation in frontal areas. Many of our results related to response inhibition strongly implicate impaired frontal lobe functioning. Our functional imaging study in high risk individuals has highlighted vulnerability in fronto- parietal circuits. The proposed project plans to further evaluate disinhibition and frontal lobe dysfunction in abstinent alcoholics by implementing novel neurophysiological paradigms that assess response activation/inhibition and their effect on course of abstinence/relapse. Novel time-frequency methods developed in our laboratory will allow us to further investigate the underlying neural oscillations and their synchrony during early and late processing during ERP tasks in several frequency bands (delta, theta, alpha, beta, and gamma), as well as their relationship to resting (baseline) EEG in alcoholics. We hypothesize that alcoholics will utilize similar/same networks for different aspects of cognitive processing, instead of specialized networks to optimize performance, and that their neural networks may not synchronize/organize effectively to produce a good signal-to-noise ratio. To further understand the biological basis of electrophysiological deficits, we propose to implement structural/functional (fMRI) imaging methods during Go/No-Go and gambling tasks and will attempt to understand the frontal circuits and localize network disruptions that are associated with response inhibition and error/outcome evaluation. Finally, we propose to use classification analyses techniques to investigate the relationships between electrophysiological measures, structural/functional indices, impulsivity and craving, that are most important in predicting relapse, and identify subgroups of alcoholics more/less likely to relapse. These findings may have important implications for cognitive, behavioral and pharmacological treatment protocols. PUBLIC HEALTH RELEVANCE R01 AA002686 The project will address important clinical challenges and basic science questions regarding the pathophysiology of cognitive and neurophysiological deficits in alcoholics that cause them to repeatedly drink despite adverse outcomes. It is of utmost importance to elucidate the underlying predisposition for the overwhelming urge to drink (craving) resulting in recidivism to inform prevention strategies. Our findings will have important implications for cognitive, behavioral and pharmacological treatment protocols.